High-dose chemotherapy combined with autologous hematopoietic cell transplantation (Auto-HCT) is considered a standard of care treatment in patients with multiple myeloma (MM). High-dose chemotherapy results in mucosal damage, mucositis, and bone marrow (BM) ablation, leading to neutropenia, neutropenic fever and infections which can result both in post-transplant morbidity and potential mortality. Therefore, interventions shortening neutropenia following Auto-HCT are necessary to reduce such transplant-related mortality and morbidity and to reduce the overall cost of Auto-HCT. These interventions should focus on improving hematopoietic stem/progenitor cell (HSPC) BM homing, as HSPCs transplanted into the circulation must cross the blood/BM endothelium barrier and lodge in the BM compartment (homing) before producing mature and functional hematopoietic cells (engraftment). We previously have demonstrated that HSPC exposure to erythropoietin (EPO) inhibits umbilical cord blood (UCB)-HSPC in vitro transmigration. In order to improve HSPC homing, we investigated hyperbaric conditions to lower EPO prior to HSPC transplantation. In a pilot clinical trial, we have shown that HBO therapy, given as a single treatment prior to UCB transplantation, was well-tolerated, resulting in significant reduction in EPO levels from baseline, also with improvement in median time to neutrophil and platelet recoveries. HBO therapy was shown to be very well tolerated in a subsequent Auto-HCT pilot study. When comparing our HBO cohort patients with our historic controls, our preliminary data indicate a significant reduction in time to neutrophil and platelet count recoveries. Also, HBO patients had significantly less mucositis and required less transfusions. Biologically, we observed a positive correlation between HBO-mediated reduction in EPO and time to neutrophil recovery in our HBO cohort. Early absolute lymphocyte count (ALC) recovery, historically attributed to NK cell recovery stimulated by IL-15, was observed in 76% of HBO patients, compared to ~50% historically. Based on our preliminary data, we hypothesize that HBO therapy significantly reduces post-transplant EPO and, as a result, improves HSPC engraftment as evidenced by improved time to neutrophil and platelet recoveries in MM patients undergoing high-dose therapy and Auto-HCT. We also hypothesize that HBO therapy up-regulates IL-15 post-transplant resulting in enhanced NK cell and ALC recoveries in MM patients undergoing Auto-HCT. To test our hypotheses, we propose a phase II randomized clinical trial in which patients will or will not receive HBO therapy. In this study, we will examine HBO effects on neutrophil, platelet, and early ALC recovery among other clinical end points. We also will examine HBO effects on plasma EPO, IL-15, and on NK cell recovery as a potential explanation for our findings. Results from this proposed trial will be used to calculate the sample size and power for a future III trial designed in order to determine HBO effects on transplant outcomes in myeloma patients undergoing high-dose therapy and Auto-HCT.